Atherothrombotic vascular disease (ATVD) remains the number one cause of death in the industrialized world, and this problem is growing annually due to the increasing rate of obesity and insulin resistance worldwide. Although oral drugs that lower systemic risk factors have been successful, there is a tremendous treatment gap that leaves up to 70% of the high-risk population at continued risk. A number of promising arterial-wall targets have been identified and validated using molecular-genetic approaches in animal models of atherosclerosis, but many of these are not amenable to oral or even standard systemic therapy.
Currently, there is no widely accepted diagnostic method to prospectively identify vulnerable plaques which could lead to ATVD. However, such prospective identification of vulnerable plaques could reduce the morbidity and mortality of thromboembolism.
Apoptosis, or programmed cell death is a genetically controlled process that contributes to the instability of atherosclerotic lesions. Apoptosis of the macrophages and of smooth muscle cells (SMC) play an important role in the process of plaque rupture and thrombus formation. Exposure of anionic phosphatidylserine (PS) on the outer leaflet of the cell membrane is one of the earliest molecular events in apoptosis. From the technical viewpoint, apoptosis will be an attractive target for the diagnosis of atherosclerotic plaques prone to thrombotic event as well as cancer.
The most common method of detecting PS on cell surface involves the use the Ca2+-dependent, PS-binding protein annexin V. For in vitro assays, the 35-kDa annexin V protein is typically labeled with a fluorescent dye, whereas radioactive and diffusion-weighted magnetic resonance imaging (MRI) techniques are employed for in vivo imaging. Although it is utilized extensively, the labeled annexin V protein is expensive and moderately unstable, and the application of diffusion-weighted MRI is limited because the method relies on strong magnetic field gradients and is sensitive to artifacts. Additionally, the magnitude of changes associated with annexin V diffusion-weighted MRI is small, making it difficult to discern the distinction between the tissue shrinkage, necrosis, and other processes that occur with an arterial wall vessel.
Other possible options for targeting PS include peptides that bind PS with high affinity and specificity and zinc 2,2′-dipicolylamine (Zn2+-DPA) coordination complexes, which have been shown to mimic the apoptosis sensing function of annexin V.
An alternative approach to detection of PS translocation (as a proxy for apoptosis) is detection of the collapse of mitochondrial membrane potential (Δψm). Δψm is a hallmark of the initiating phase of apoptosis. Unlike the transient nature of PS exposure, collapse of Δψm is an ongoing process. Δψm monitoring could offer an effective strategy for detection of vulnerable plaques by monitoring apoptotic macrophages atherosclerotic plaques of arterial-wall leading to early diagnosis and aggressive management to help prevent or slow the progression by delivering therapeutics that exhibit direct effects on macrophage inflammation related to ATVD or coronary heart disease (CHD) in general.